Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability

Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability. Am J Physiol Renal Physiol 313: F174 –F183, 2017. First published March 29, 2017; doi:10.1152/ajprenal.00482.2016.—The goals of this study were to 1) develop a computational model of solute transport and oxygenation in the kidney of the female spontaneously hypertensive rat (SHR), and 2) apply that model to investigate sex differences in nitric oxide (NO) levels in SHR and their effects on medullary oxygenation and oxidative stress. To accomplish these goals, we first measured NO synthase (NOS) 1 and NOS3 protein expression levels in total renal microvessels of male and female SHR. We found that the expression of both NOS1 and NOS3 is higher in the renal vasculature of females compared with males. To predict the implications of that finding on medullary oxygenation and oxidative stress levels, we developed a detailed computational model of the female SHR kidney. The model was based on a published male kidney model and represents solute transport and the biochemical reactions among O2, NO, and superoxide (O2 ) in the renal medulla. Model simulations conducted using both male and female SHR kidney models predicted significant radial gradients in interstitial fluid oxygen tension (PO2) and NO and O2 concentration in the outer medulla and upper inner medulla. The models also predicted that increases in endothelial NO-generating capacity, even when limited to specific vascular segments, may substantially raise medullary NO and PO2 levels. Other potential sex differences in SHR, including O2 production rate, are predicted to significantly impact oxidative stress levels, but effects on NO concentration and PO2 are limited.This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-106102 to A. T. Layton, and by American Heart Association Grant 14GRNT20480199 to J. C. Sullivan. (R01-DK-106102 - National Institute of Diabetes and Digestive and Kidney Diseases; 14GRNT20480199 - American Heart Association)Accepted manuscrip

Apatite-Polymer Composites for the Controlled Dual Delivery of BMP-2 and BMP-6 for Bone Tissue Engineering

The release of growth factors from tissue engineering scaffolds provides signals that influence the migration, differentiation, and proliferation of cells. The incorporation of a drug delivery platform that is capable of tunable release will give tissue engineers greater versatility in the direction of tissue regeneration. We have prepared a novel composite of two biomaterials with proven track records - apatite and poly(lactic-co-glycolic acid) (PLGA) – as a drug delivery platform with promising controlled release properties. These composites have been tested in the delivery of a model protein, bovine serum albumin (BSA), as well as therapeutic proteins, recombinant human bone morphogenetic protein-2 (rhBMP-2) and rhBMP-6. The controlled release strategy is based on the use of a polymer with acidic degradation products to control the dissolution of the basic apatitic component, resulting in protein release. Therefore, any parameter that affects either polymer degradation or apatite dissolution can be used to control protein release. We have modified the protein release profile systematically by varying the polymer molecular weight, polymer hydrophobicity, apatite loading, apatite particle size, and other material and processing parameters. Biologically active rhBMP-2 was released from these composite microparticles over 100 days, in contrast to conventional collagen sponge carriers, which were depleted in approximately 2 weeks. The released rhBMP-2 was able to induce elevated alkaline phosphatase and osteocalcin expression in pluripotent murine embryonic fibroblasts. To augment tissue engineering scaffolds with tunable and sustained protein release capabilities, these composite microparticles can be dispersed in the scaffolds in different combinations to obtain a superposition of the release profiles. We have loaded rhBMP-2 into composite microparticles with a fast release profile, and rhBMP-6 into slow-releasing composite microparticles. An equi-mixture of these two sets of composite particles was then injected into a collagen sponge, allowing for dual release of the proteins from the collagenous scaffold. The ability of these BMP-loaded scaffolds to induce osteoblastic differentiation in vitro and ectopic bone formation in a rat model is being investigated. We anticipate that these apatite-polymer composite microparticles can be extended to the delivery of other signalling molecules, and can be incorporated into other types of tissue engineering scaffolds.Singapore-MIT Alliance (SMA

Informal support of older persons under different living arrangements : a case study in Tuen Mun, Hong Kong

This research focuses on sources of informal support for elderly people under different living arrangements in Hong Kong, with Tuen Mun new town as a case study. The thesis attempts to assess the attitudes of elderly people to the needs and adequacy of the informal support provided by their family members and their social support network. It also attempts to assess older people\u27s views of the incentives and motivations for children to provide support to their elderly parents. In this way, it hopes to throw light on conceptual issues including the role of filial piety and changes in intergenerational relations, especially in the context of Hong Kong as an example of a modernizing Asian society. A social support network can provide a number of functions. It can provide an elderly person with both instrumental support and non-instrumental support in later life. An informal support network consists mainly of networks of family members, neighbours and friends. However as societies modernize, there are likely to be changes in family structure and functions, in addition to the changes in traditional values; indeed, modernization is often felt to have weakened the care-giving function of the family. To investigate the social support consequences of these changes, this research adopts a qualitative approach, to attempt to examine older persons\u27 attitude to the motivation and feelings behind provision of informal support under a range of living arrangements: alone, with or without spouse or children. In-depth interviews were conducted with 50 elderly people in public housing estates. Triangulation was carried out with data from individual respondents, two focus groups and key informants, as well as the published literature. In this way, the reliability of the research and a fuller picture of the informal support of elderly people were achieved. The main findings of the research were that certain forms of support require close proximity whilst others can be performed at a distance, and those co-residing with elderly relatives may be more aware of their full range of needs. Therefore, the factor of proximity, especially living arrangements (and geographical distance from potential caregivers) and the quality of relationships between the potential care-giver and potential care-receiver appear to affect the needs for and provision of support to older persons. Furthermore, the research found that there could be important interactions between various components of informal support. In addition, the research found that the traditional value of filial piety has been modified and in many ways eroded, so a modem interpretation of the traditional concept may be emerging

Aurora in the Polar Cap: A Review

This paper reviews our current understanding of auroral features that appear poleward of the main auroral oval within the polar cap, especially those that are known as Sun-aligned arcs, transpolar arcs, or theta auroras. They tend to appear predominantly during periods of quiet geomagnetic activity or northwards directed interplanetary magnetic field (IMF). We also introduce polar rain aurora which has been considered as a phenomenon on open field lines. We describe the morphology of such auroras, their development and dynamics in response to solar wind-magnetosphere coupling processes, and the models that have been developed to explain them

Synthesis and characterization of hybrid organic-inorganic materials based on sulphonated polyamideimide and silica

The preparation of hybrid organic–inorganic membrane materials based on a sulphonated polyamideimide resin and silica filler has been studied. The method allows the sol–gel process to proceed in the presence of a high molecular weight polyamideimide, resulting in well dispersed silica nanoparticles (<50 nm) within the polymer matrix with chemical bonding between the organic and inorganic phases. Tetraethoxysilane (TEOS) was used as the silica precursor and the organosilicate networks were bonded to the polymer matrix via a coupling agent aminopropyltriethoxysilane (APTrEOS). The structure and properties of these hybrid materials were characterized via a range of techniques including FTIR, TGA, DSC, SEM and contact angle analysis. It was found that the compatibility between organic and inorganic phases has been greatly enhanced by the incorporation of APTrEOS. The thermal stability and hydrophilic properties of hybrid materials have also been significantly improved

Developing a risk governance framework on radiological emergency, preparedness, and response for emergency responders: protocol for a mixed methods study

Background: Risk governance involves processes and mechanisms to understand how risk decisions are taken and executed. This concept has gained a reputation over time as being essential for emerging comprehensive management that defines the success of an organization. While guiding documents that explain the use of risk management related to nuclear safety and security are available worldwide, few locally conducted studies have explained risk governance practices in areas where hazard usage is known, such as in radiological emergencies. Objective: This paper describes a protocol that was used to determine several factors that influence emergency responders' perceptions toward radiological risk practices and visualize the risk radiological framework for emergency preparedness and response. Methods: A mixed methods study with a convergent design was performed. A qualitative analysis was performed using a case study approach where 6 key informants were purposely sampled for in-depth interview, and a cross-sectional study involving a self-administered questionnaire was conducted among approximately 260 emergency respondents from national regulatory, research, and services organizations. NVivo (version 12, QSR International) was used to analyze the interview transcripts and emerging themes were identified through abductive coding. Simultaneously, multiple logistic regression analysis was used to determine significant predictors that form the equation model. Results: The study is still underway. Qualitative findings were based on transcript-coding that informed the relevant thematic analysis, while statistical analyses including multiple logistic regression analysis measured the adjusted odds ratio of significant variables for the equation model. The study is expected to conclude in late 2021. Conclusions: Important emerging themes and significant factors that are related to the emergency responders' perceptions regarding radiological governance practices were determined through the convergent design. This potentially facilitated the development of a plausible radiological risk governance framework. Furthermore, our results will provide key insights that can be used in future studies

Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo.

BACKGROUND Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. METHODS To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. RESULTS We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05×10−23) and class II molecules (P=4.50×10−34), PTPN22 (P=1.31×10−7), LPP (P=1.01×10−11), IL2RA (P=2.78×10−9), UBASH3A (P=1.26×10−9), and C1QTNF6 (P=2.21×10−16). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07×10−15) and GZMB (P=3.44×10−8), and in a locus containing TYR (P=1.60×10−18), encoding tyrosinase. CONCLUSIONS We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma

Changes in serum proteomic patterns by presurgical alpha-tocopherol and L-selenomethionine supplementation in prostate cancer

BACKGROUND: Evidence of the chemopreventive effects of the dietary antioxidants alpha-tocopherol (vitamin E) and l-selenomethionine (selenium) comes from secondary analysis of two phase III clinical trials that found treatment with these antioxidants reduced the incidence of prostate cancer. To determine the effects of selenium and vitamin E in blood and prostate tissue, we undertook a preoperative feasibility study complementary to the currently ongoing Selenium and Vitamin E Cancer Prevention Trial. METHODS: Forty-eight patients with clinically localized prostate cancer enrolled on this 2 x 2 factorial design study were randomized to take selenium, vitamin E, both, or placebo for 3 to 6 weeks before prostatectomy. Sera were collected from patients before and after dietary supplementation. Thirty-nine patients were evaluable, and 29 age-matched disease-free men served as controls. Mass profiling of lipophilic serum proteins of lower molecular weight (2-13.5 kDa) was conducted, and mass spectra data were analyzed using custom-designed software. RESULTS: Weighted voting analyses showed a change in sera classification from cancerous to healthy for some patients with prostate cancer after dietary intervention. ANOVA analysis showed significantly different treatment effects on prediction strength changes among the four groups at a 95% confidence level. Eliminating an outlying value and performing post hoc analysis using Fisher\u27s least significant difference method showed that effects in the group treated with the combination were significantly different from those of the other groups. CONCLUSION: In sera from patients with prostate cancer, selenium and vitamin E combined induced statistically significant proteomic pattern changes associated with prostate cancer-free status

Reduced Satb1 expression predisposes CD4+ T conventional cells to Treg suppression and promotes transplant survival

Limiting CD4+ T cell responses is important to prevent solid organ transplant rejection. In a mouse model of costimulation blockade-dependent cardiac allograft tolerance, we previously reported that alloreactive CD4+ conventional T cells (Tconvs) develop dysfunction, losing proliferative capacity. In parallel, induction of transplantation tolerance is dependent on the presence of regulatory T cells (Tregs). Whether susceptibility of CD4+ Tconvs to Treg suppression is modulated during tolerance induction is unknown. We found that alloreactive Tconvs from transplant tolerant mice had augmented sensitivity to Treg suppression when compared with memory T cells from rejector mice and expressed a transcriptional profile distinct from these memory T cells, including down-regulated expression of the transcription factor Special AT-rich sequence-binding protein 1 (Satb1). Mechanistically, Satb1 deficiency in CD4+ T cells limited their expression of CD25 and IL-2, and addition of Tregs, which express higher levels of CD25 than Satb1-deficient Tconvs and successfully competed for IL-2, resulted in greater suppression of Satb1-deficient than wild-type Tconvs in vitro. In vivo, Satb1-deficient Tconvs were more susceptible to Treg suppression, resulting in significantly prolonged skin allograft survival. Overall, our study reveals that transplantation tolerance is associated with Tconvs’ susceptibility to Treg suppression, via modulated expression of Tconv-intrinsic Satb1. Targeting Satb1 in the context of Treg-sparing immunosuppressive therapies might be exploited to improve transplant outcomes